1. Field of the Invention
This invention relates to novel three-layered pharmaceutical film preparations and processes for the production thereof. More specifically, this invention relates to the three-layered pharmaceutical film preparations which comprise one drug-storing middle layer composed of water soluble polymers and therapeutically active ingredients (prostaglandin analogues), and two release-controlling layers on both sides of the said middle layer, composed of water soluble polymers, characterized by that the prostaglandin analogues contained therein exhibit the desired long-lasting release pattern, further fully satisfying the purpose that drug preparations which have very high biological availability and are effective and safe should be supplied, as well as the novel processes for production thereof.
2. Description of the Prior Art
Various techniques for releasing drug for an extended period of time have heretofore been reported in the literature. For instance, there are known coating methods to maintain release for an extended period of time, as found mainly in oral tablets, intravaginally devices, drug release devices utilizing the osmotic pressure and dispensers utilizing semipermeable membranes or porous membranes etc. In more recent years, there have also been reported the development of polymers for achieving long-lasting release intended for topical applications, long-lasting films and containers for releasing the drug quantitatively by release from one side; in any case, however, they have disadvantages that high levels of techniques and equipment are required and that the form of that device (preparation) is retained even in the vital body (administration site) to give an extraneous feel to the human. Further, they also have such disadvantages that the expected drug efficacy is difficult to obtain because the stability of the active ingredient is adversely affected, the biological availability is low and the like. As a method eliminated these disadvantages, there are film preparations and preparations like cellulose fiber to obtain long-lasting release by using cellulose ether etc. soluble in body fluid (see Japanese Patent Kokai No. 49-133519, Derwent No. 47633V). Although the form of the said preparations is not retained in the administration site, they have disadvantages that high levels of techniques and equipment, and further high temperature in the production process are required, and, therefore, it is considered that the stability of the active ingredient is adversely affected by high temperature in case of the production of the preparation containing prostaglandin analogues.
In more recent years, we have proposed milti-layered pharmaceutical film preparations which comprise water soluble polymer bases and water insoluble polymer bases, for the purpose of maintaining the release of a drug for an extended period of time (see Japanese Patent Kokai No. 57-70816, Derwent No. 35619E). However, though these pharmaceutical film preparations are improved, they still have disadvantages that the biological availability is not sufficient, the lasting time of release is short, and the release tends to be "sigmoid release" (S-shaped release) and the like. Therefore, it can not be said that they are satisfactory film preparations.
On the other hand, there are known several methods for the production of a film using hydroxypropyl cellulose (abbreviated HPC hereafter). That is to say, as a process for the production of the films using HPC, there are known a process dissolving HPC in a suitable organic solvent and then evaporating the solvent, and a process dissolving HPC in water and then evaporating water (see Japanese Patent Kokai No. 56-36173, Derwent No. 43052W). The said processes are very useful when HPC used has relatively small molecular weight, e.g. 30,000-150,000 and low viscosity. However, there is a possibility to produce various problems when HPC used has the molecular weight of 250,000-400,000 and high viscosity.
For example, practically speaking, the upper limit of the solubility of HPC having the molecular weight of 250,000-400,000 (abbreviated HPC--H hereafter) in water or methanol is 4% and, therefore, a HPC--H solution having a thickness of 1 mm becomes the HPC--H film having a thickness of only about 0.04 mm after evaporation. Accordingly, it is necessary to pour out a HPC--H solution having a thickness of about 7.5 mm in order to obtain a HPC--H film having a thickness of 0.3 mm which is preferable thickness for the release-controlling layers in the pharmaceutical film preparation of the present invention. However, the increase of a volume of the solvent used causes various problems that a film having uniform thickness can not be obtained, that it takes a lot of time to dry the film, that it is difficult to dry completely, and further, that the environment in or out of the laboratory is polluted and the like. Particularly, it is presumed that the difficulty in removing bubbles owing to its high viscosity becomes a large obstacle to the mass production.